Process for the preparation of an indole derivative

ABSTRACT

A process for the preparation of methyl 2-(3-chloropropoxy)-indole-3-carboxylate, which comprises reacting a 3-chloro-3-carboxylate indole compound with 3-chloropropanol in the presence of an acid having a pKa of from 0 to 2.

[0001] This invention relates to a new synthetic process to a compoundhaving pharmacological activity.

[0002] WO 93/18036 (SmithKline Beecham plc) describes certain indolecompounds having 5-HT₄ receptor antagonist activity including thecompound of formula (I)

[0003] and its pharmaceutically acceptable salts. This compound isN-[(1-^(n)butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide,referred to herein by its code number SB-207266, (the hydrochloride saltis SB-207266-A), which is being developed by SmithKline Beecham plc asthe active ingredient in a medicament for treatment of irritable bowelsyndrome.

[0004] Example 3 of WO 93/18036 describes a method of preparation ofSB-207266-A from N-[(1-^(n)butyl-4-piperidyl)methyl]indole-3-carboxamide(i.e. the compound corresponding to SB-207266, without the oxazinomoiety), by reacting with N-chlorosuccinimide and 3-bromo-1-propanol,followed by treatment with sodium carbonate.N-[(1-^(n)butyl-4-piperidyl)methyl]indole-3-carboxamide is prepared bycoupling N-(1-^(n)butyl-4-piperidyl)methylamine with aindole-3-carboxylic acid.

[0005] WO 98/07728 (SmithKline Beecham plc) describes a process forpreparing SB-207266-A which involves the use of theN-(1-^(n)butyl-4-piperidyl)methylamine intermediate at a later stage inthe process thus resulting in an increased yield of SB-207266-A relativeto the amount of this intermediate, which is relatively expensive toproduce. In particular, the alternative process comprises the reactionof of N-(1-^(n)butyl-4-piperidyl)methylamine with a compound of formula(A):

[0006] wherein R is alkyl, such as methyl or ethyl.

[0007] The compound of formula (A) wherein R is methyl is methyl3,4-dihydro-2H-[1,3]-oxazino[3,2-α]indole-10-carboxylate.

[0008] WO98/07728 also describes the preparation of the oxazinoindolecompound of the formula (A) from the corresponding indole by reactionwith N-chlorosuccinimide and a 3-halo-propanol, such as 3-chloropropanolor 3-bromopropanol followed by cyclisation of the intermediate (B) bytreatment with base in a suitable solvent.

[0009] The Description in the latter specification describes in moredetail the the preparation of compound (B) from the corresponding methylindole-3-carboxylate by reaction of the latter with N-chlorosuccinimidein the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) to form anintermediate of formula (C):

[0010] and subsequent reaction of (C) with 3-chloropropanol in thepresence of methanesulphonic acid.

[0011] We have now found that the use of an acid having a pKa of from 0to 2, especially trichloroacetic acid, in place of methanesulphonic acidresults in significant advantages for the commercial operation of theprocess.

[0012] According to a feature of the present invention we provide aprocess for the preparation of the compound of formula (B) above, namelymethyl 2-(3-chloropropoxy)-inodole-3-carboxylate, which comprisesreacting a compound of formula (C) with 3-chloropropanol in the presenceof an acid having a pKa of from 0 to 2, especially trichloroacetic acid.

[0013] Other acids which may be used in accordance with the invention inaddition to trichloroacetic acid include dichloroacetic acid andtrifluoroacetic acid.

[0014] The use of the above-defined acid such as trichloroacetic acid inplace of methanesulphonic acid has been found to increase significantlythe overall yield of the process. The former acid also has the advantageover the latter that its use results in the formation of lower levels ofthe corresponding 2-methoxy compound, as an impurity.

[0015] The reaction is conveniently effected in an organic solvent suchas dichloromethane or chloroform, at a temperature in the range −20° C.to +10° C., for example using a catalytic amount of the acid. Theresulting product of formula (B) can be used for the next stage in thesynthesis of SB-207266 e.g as described in WO 98/07728.

[0016] The following Example illustrates the invention.

EXAMPLE Methyl 2-(3-Chloropropoxy)-Indole-3-Carboxylate (Formula (B))

[0017] A mixture of methyl indole-3-carboxylate and dichloromethane iscooled to 0° C. 1,4-dimethylpiperazine (0.55 eq.) andN-chlorosuccinimide (1.1 eq) are added and the mixture left to stir fortwo hours to give a slurry containing the compound of formula (C) above.The resulting slurry is added to a solution of 3-chloropropanol (1.1 eq)and trichloroacetic acid (0.12 eq) in dichloromethane, maintaining thetemperature below 0° C. The reaction mixture is left to stir for half anhour, then washed with 10% aqueous sodium carbonate, 0.5 M hydrochloricacid and water. The organic solution is dried over sodium sulphate,filtered and the solvent evaporated. Toluene is added and the mixturestirred at 0-5° C. for one hour. The product is then filtered, washedwith toluene and dried to give the title product in 83% yield.

1 and 2 (Cancelled)
 3. A process for preparingN-[(1-^(n)butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide,i.e. the compound of Formula (I):

or a pharmaceutically acceptable salt thereof, which process comprises(a) preparing methyl 2-(3-chloropropoxy)-indole-3-carboxylate, i.e. thecompound of formula (B):

by reacting a compound of formula (C)

with 3-chloropropanol in the presence of an acid having a pKa of from 0to 2; and (b) using the resulting methyl2-(3-chloropropoxy)-indole-3-carboxylate of formula (B) in the nextstage in the synthesis of theN-[(1-^(n)butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamideor the pharmaceutically acceptable salt thereof.
 4. A process as claimedin claim 3 wherein in step (a) the acid is trichloroacetic acid,dichloroacetic acid and/or trifluoroacetic acid.
 5. A process as claimedin claim 3 wherein in step (a) the acid is trichloroacetic acid.
 6. Aprocess as claimed in claim 3 wherein the reaction in step (a) iseffected in an organic solvent.
 7. A process as claimed in claim 6wherein in step (a) the organic solvent is dichloromethane orchloroform.
 8. A process as claimed in claim 3 wherein the reaction instep (a) is effected in an organic solvent at a temperature in the range−20° C. to +10° C.
 9. A process as claimed in claim 4 wherein thereaction in step (a) is effected in an organic solvent at a temperaturein the range −20° C. to +10° C.
 10. A process as claimed in claim 8wherein in step (a) the organic solvent is dichloromethane orchloroform.
 11. A process as claimed in claim 9 wherein in step (a) theorganic solvent is dichloromethane or chloroform.
 12. A process asclaimed in claim 6 wherein the reaction in step (a) is effected using acatalytic amount of the acid.
 13. A process as claimed in claim 8wherein the reaction in step (a) is effected using a catalytic amount ofthe acid.
 14. A process as claimed in claim 9 wherein the reaction instep (a) is effected using a catalytic amount of the acid.
 15. A processas claimed in claim 11 wherein the reaction in step (a) is effectedusing a catalytic amount of the acid.
 16. A process as claimed in claim3 comprising, in step (b), cyclisation of the intermediate (B) (themethyl 2-(3-chloropropoxy)-indole-3-carboxylate) by treatment with basein a solvent to prepare a compound of formula (A):

wherein R is methyl, which compound of formula (A) is methyl3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate.
 17. A processas claimed in claim 16, comprising, in step (b): reactingN-(1-^(n)butyl-4-piperidyl)methylamine with the methyl3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate of formula (A)to prepare theN-[(1-^(n)butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamideof formula (I); and optionally preparing a pharmaceutically acceptablesalt of theN-[(1-^(n)butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide.18. A process as claimed in claim 13 comprising, in step (b),cyclisation of the intermediate (B) (the methyl2-(3-chloropropoxy)-indole-3-carboxylate) by treatment with base in asolvent to prepare a compound of formula (A):

wherein R is methyl, which compound of formula (A) is methyl3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate.
 19. A processas claimed in claim 18, comprising, in step (b): reactingN-(1-^(n)butyl-4-piperidyl)methylamine with the methyl3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate of formula (A)to prepare theN-[(1-^(n)butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamideof formula (I); and optionally preparing a pharmaceutically acceptablesalt of theN-[(1-^(n)butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide.20. A process as claimed in claim 3, wherein step (b) comprisespreparing the hydrochloride salt ofN-[(1-^(n)butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide.21. A process as claimed in claim 13, wherein step (b) comprisespreparing the hydrochloride salt ofN-[(1-^(n)butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide(SB-207266-A).
 22. A process as claimed in claim 17, wherein step (b)comprises preparing the hydrochloride salt ofN-[(1-^(n)butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide(SB-207266-A).
 23. A process as claimed in claim 19, wherein step (b)comprises preparing the hydrochloride salt ofN-[(1-^(n)butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide.